Amyloid-β (Aβ) deposits are a well known pathological hallmark for Alzheimer's disease (AD). Their formations arise from aggregated peptides Aβ40 and Aβ42, which are generated from amyloid peptide precursor (APP) by cleaving with β- and γ-secretases {11; 15}. Normally, the concentrations of the generated Aβ40 and Aβ42 monomers are maintained at a reasonable level through the balance between generation and clearance. Upon the initiation of AD, however, the equilibrium moves towards accumulating of Aβ monomers. Consequently, the monomers begin to form fibrils upon stimulation with various factors such as stress, overload of metal ions including ferric, copper and zinc. Finally, the fibrils develop into extracellular deposits (senile plaques) of micron size in the progress of aging {12; 10; 13; 3; 14}. Although, it is controversial whether Aβ deposits precede and induce the neuronal atrophy {15} recent evidence indicates that Aβ plaques are the herald and critical mediator of neuritic pathology {2}.
Tau fibrils formation is another widely considered pathological hallmark for AD. They represent intracellular fibrils and tangles generated from helical parallel filament (HPF) protein {18; 19}. Although both Aβ plaques and tau fibrils are definite signs for AD, it is not yet clear whether Aβ plaques formation and Tau generation are linked to each other, or they exist as parallel pathological pathways {22; 30; 22; 21}.
Currently, the diagnosis of AD mainly relies on memory and behavior tests, and the final confirmation is usually based on postmortem analysis. Both memory and behavior tests, however, are not reliable and not suitable for the early detection because of the lack of noticeable syndrome at the early stage {20}. Therefore, the early detection of AD still presents a challenge. Molecular imaging, a molecular level and high sensitivity detecting technology, represents a promising approach to face this challenge. Molecular MR imaging, optical imaging and PET imaging have been employed as modalities for the early detection of AD pathology, and considerable progresses has been achieved in recent years {46; 24; 1; 7; 25; 27; 26; 110; 111; 112; 28}. Direct MRI visualization of Aβ plaques in AD brain tissue was reported, using MR microscopy and very long scanning time (24 hours) {26}. Targeting MRI detecting Aβ plaques with antibody conjugated with magnetic probes was also reported, but it required transient BBB opening {28}. Poduslo et al reported that a conjugate of gadolinium and modified Aβ40 segment (Aβ30) had BBB penetrating ability and was suitable for in vivo MRI visualization of Aβ plaques {27}.
In addition, Higuchi et al claimed that by using an Aβ plaque specific small molecular probe with fluoride, they were able to detect the deposit in transgenic mice by 1H MRI and 19F MRI {25}. Although these studies indicate that molecular MRI is a promising diagnostic modality, its low sensitivity could be an obstacle for its application in clinic. In recent years, researches have demonstrated that PET can be used as an imaging modality to detect AD pathology; however, its high cost and narrow availability of contrast agents prevent its broad usage {23}. Molecular optical imaging is a promising modality for early AD pathological detection. Multiphoton and near infrared imaging are the most used optical imaging modalities, based on the fluorescent property of the probes. Although multiphoton microscopy could be very useful in animal research, it is invasive and only provides very small field-of-view information {23; 7; 5; 6; 8}.
Near Infrared Imaging (NIR) is a very attractive tool for early AD detection because of its acceptable depth penetration, non-invasive operation, and inexpensive instrumentation. Several non-NIR molecules that specifically bind to senile plaques have been reported for multiphoton imaging and histological studies; near-infrared probes, however, are few {24; 3}. NIAD-4 was reported as a potential senile plaque-specific two-photon microscopy probe that could be used as a NIR probe. Most importantly, it showed significant fluorescence intensity increase upon binding to Aβ aggregates in in vitro test. Therefore, this type of molecule could be referred as a “smart” probe. NIAD-4 and its analogues are currently under investigation for senile plaque monitoring by measuring life time change {7; 3} Additionally, Chang et al reported that some styryl dyes could be “turned on” upon incubating with Aβ aggregates, but these compounds may have little chance penetrating BBB because of their large polarity {29}.
Curcumin, a brightly colored powder, is the principal curcuminoid of the Indian curry spice turmeric, and consumed daily for thousand of years in India and other regions. Curcumin is known for its antitumor, antioxidant, antiarthritic and anti-inflammatory properties {30; 32; 31; 33}. It has been utilized as an anti-amyloid agent as well {5; 157}. In 2004, Yang et al reported that curcumin could be used as a histological staining reagent for senile plaques and showed that curcumin could decrease amyloid deposits in vivo {34}. Further, Garcia-Alloza et al. demonstrated by two-photon imaging, that curcumin could be visualized in vivo and could prevent the progress of amyloid plaque forming in APP/Tau transgenic mice model {5}. In addition, Ryu pointed out that curcumin derivatives were suitable for amyloid deposit monitoring by PET {35}. All of the studies showed that curcumin is very specific for amyloid plaque and displays high affinity binding for Aβ aggregates. However, curcumin is not practical for in vivo NIR imaging because of its short emission wavelength and low lipophilicity (log P<2){35}.
As can be appreciated, it would be desirable to obtain new imaging agents useful for the detection of amyloid-β plaques in human subjects. In particular, it is desirable to utilize near-infrared (NIR) imaging as a sensitive, low cost and non-invasive approach for the early detection of AD. To meet this objective, “smart” probes that can be “turned on” with emission in the NIR imaging window are highly sought after in the medical imaging field.